Regulation of ALT-associated homology-directed repair by polyADP-ribosylation

Hoang, Song My; Kaminski, Nicole; Bhargava, Ragini; Barroso-González, Jonathan; Lynskey, Michelle Lee; García-Expósito, Laura; Roncaioli, Justin L.; Wondisford, Anne R.; Wallace, Callen T.; Watkins, Simon C.; James, Dominic I.; Waddell, Ian D.; Ogilvie, Donald; Smith, Kate; Leprevost, Felipe da Veiga; Mellacharevu, Dattatreya; Nesvizhskii, Alexey I.; Li, Jianfeng; Ray-Gallet, Dominique; Sobol, Robert W.; Almouzni, Geneviève; O’Sullivan, Roderick J.

doi:10.1038/s41594-020-0512-7

Cited by 37 publications

(22 citation statements)

References 54 publications

(82 reference statements)

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“…Furthermore, PARG activity was recently demonstrated to play a critical role in telomere extension through the alternative lengthening of telomeres (ALT) mechanism in cancer cells, including U2OS ( Hoang et al., 2020 ). Therefore, we decided to explore whether the additional loss of ARH3 would further impair this mechanism that is crucial for the survival of these cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

et al. 2021

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Section: Resultsmentioning

confidence: 99%

Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

et al. 2021

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“…H3.3 G34R/V has, however, only been shown to obstruct SETD2 activity in cis 66,67 and this conjecture is therefore dependent on the mutant histone being incorporated into telomeric chromatin. In support of this possibility, recent work has shown that in the absence ATRX/DAXX, the histone H3.3 chaperone HIRA is enriched at ALT telomeres as an adaptive response to allow the deposition of histone H3.3 at telomeres 68 . A second mutation in histone H3.3 at lysine 27 to methionine (K27M) is also highly coincident with ATRX loss and inhibits the catalytic activity of PRC2 16,45,67 .…”

Section: Discussionmentioning

confidence: 95%

Induction of the ALT pathway requires loss of ATRX-DAXX in concert with genotoxic lesions at telomeres

Clynes

Goncalves

Kent

et al. 2021

Preprint

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A key requisite for indefinite growth of cancer cells is the ability to continuously elongate telomeres to circumvent the onset of senescence or apoptosis. In approximately 10 – 15% of cancers this is achieved through the Alternative Lengthening of Telomeres (ALT) pathway, a Break Induced Replication (BIR) mediated mechanism of telomere copying. ATRX has emerged as the key tumour suppressor in ALT cancers but its loss is insufficient to drive induction of the pathway. Here, we report that depletion of ATRX and/or DAXX in the presence of various genotoxic agents is sufficient to induce ALT. Moreover, co-deletion of ATRX and SETD2, commonly mutated in high grade gliomas (HGGs), elicits induction of ALT. Mechanistically, SETD2 restricts the accumulation of telomeric R-loops, which, in the absence of ATRX, leads to fork collapse and the loss of telomere sister chromatid cohesion. Cumulatively this provides a substrate for out of register BIR and telomere lengthening.

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“…Whether nuclear F-actin promotes clustering of ALT telomeres, or their relocation to PML-NBs, is unknown. However, APB formation in ALT cells was suppressed when APR2/3 activity was inhibited, indicative of a link between nuclear cytoskeletal forces and ALT-activity [96].…”

Section: Hdr In Pml-nbsmentioning

confidence: 98%

Chromatin mobility and relocation in DNA repair

Lamm

Rogers

Cesare

2021

Trends in Cell Biology

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The nucleus is a dynamic environment containing chromatin, membraneless organelles, and specialized molecular structures at the nuclear membrane. Within the spectrum of DNA repair activities are observations of increased mobility of damaged chromatin and the displacement of DNA lesions to specific nuclear environments. Here, we focus on the role that nuclear-specific filamentous actin plays in mobilizing damaged chromatin in response to DNA double-strand breaks and replication stress. We also examine nuclear pore complexes and promyelocytic leukemia-nuclear bodies as specialized platforms for homology-directed repair. The literature suggests an emerging model where specific types of DNA lesions are subjected to nuclear-derived forces that mobilize damaged chromatin and promote interaction with repair hubs to facilitate specialized repair reactions. Nuclear dynamics in genome stabilityThe nucleus is now appreciated as a dynamic entity subjected to regulated physical alteration in response to cellular stress. A core nuclear function is to maintain genome integrity by facilitating repair of the genetic material when the need arises. Recent advances have illuminated added levels of regulation in DNA repair processes. Namely, the discovery of nuclear-specific cytoskeleton forces that potentiate movement of damaged chromatin and the directed displacement of DNA lesions to nuclear structures that function as hubs of specialized repair reactions. While there is a growing appreciation for chromatin mobility in DNA repair, the cellular mechanisms that dictate when, how, and which types of genomic lesions are mobilized, and which repair processes ensue thereafter, are continuing to be elucidated.

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Regulation of ALT-associated homology-directed repair by polyADP-ribosylation

Cited by 37 publications

References 54 publications

Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

Induction of the ALT pathway requires loss of ATRX-DAXX in concert with genotoxic lesions at telomeres

Chromatin mobility and relocation in DNA repair

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